The New Insight of Vasculitis and Allergy
Vasculitis is an inflammatory process of the blood vessels that appears as palpable purpuric papules. A common form is known as leukocytoclastic vasculitis (process mediated by neutrophils). The term vasculitis identifies complex medical conditions characterized by blood vessel inflammation and damage. Serious complications result when the vascular lumen is compromised and ischemia results. Vasculitis may be a primary disease or a manifestation of another disease . Typically, vasculitis is systemic. Most vasculitis syndromes affect some tissues or organs more than others. Occasionally the disorder is confined to a single organ, such as the skin.
The diversity of vasculitis syndromes make these conditions a clinical concern for general-medicine physicians as well as specialists. Vasculitis syndromes most likely to be encountered by allergists/immunologists are hypersensitivity vasculitis; ANCA associated vasculitis, including Wegener’s granulomatosis and Churg-Strauss vasculitis (allergic angitis and granulomatosis); and temporal arteritis.
Because the etiology of most vasculitic syndromes is unknown, the development of definitive therapy for these conditions is hampered. Nevertheless, progress continues in refining immunosuppressive treatment and in improving the monitoring of therapy. In addition, diagnostic classification schemes continue to evolve and new testing modalities—particularly antineutrophil cytoplasmic antibody (ANCA) testing—are proving to be clinically useful.
In vasculitis, lesions are purpuric and do not blanch due to blood extravasation from damaged vessels. They are palpable because of inflammation and edema. Vasculitis is commonly associated with systemic conditions such as sepsis and collagen vascular diseases. They can also be due to drug reactions.
Treatment is geared toward the underlying cause or removal or the offending agent. Immunosuppressants are often used to control the inflammatory process.
Microscopically, vasculitis shows inflammatory destruction of a blood vessel wall and can affect different sizes of vessels. The inflammation within the vessel wall can be acute with neutrophils and/or eosinophils, can be granulomatous and also lymphocytic. Usually there is leakage of red cells into the dermis from the damaged vessel (red cell extravasation) and fragmentation of the inflammatory cells involved (leukocytoclasis). Fibrinoid type necrosis of vessel walls can occur. Leukocytoclastic Vasculitis (LCV) is a common type of hypersensitivity vasculitis affecting the small superficial capillaries of the dermis with infiltrates of neutrophils and sometimes eosinophils.
Vasculitis is characterized by inflammation in blood vessel walls Systemic vasculitis, of course, as we are all aware, is a rather complex issue. It is inflammation of vessel walls. It is not inflammation around vessels; it is inflammation of vessel walls. The vasculitis that affect the kidney most often are necrotizing vasculitides that affect parenchymal arteries and also in fact very often vessels other than arteries. You could say vessels smaller than arteries, but it’s really more definitive to say vessels other than arteries. Today we are really going to be concerned with necrotizing vasculitis affecting arteries and other smaller vessels. Large vessel disease. There are large vessel vasculitides that occasionally affect the kidney. These vasculitides by definition affect the aorta and its major branches; and therefore, the major impact on the kidney is through the induction of hypertension.
Renal vascular hypertension because of injury to the aorta at the ostium or involvement of some of the larger arterial radicals leading to the kidney is the major problem in patients with giant cell arteritis and Takayasu’s arteritis. I’m not going to spend any more time discussing those large vessel vasculitides. Medium and small vessel vasculitides Really the more difficult classification and therefore diagnostic problems are with vessels that affect the parenchymal arteries, arterioles, the glomerular capillaries and even other vascular structures, such as the vasa recta within the kidney. So we are going to be concerned with these so-called medium-sized vessel vasculitides, which, by at least the definition at I prefer, indicates that they involve arteries; and small-vessel vasculitides, which means that they involve vessels other than arteries, which of course means vessels smaller than arteries, such as capillaries and venules.
Some of the earliest investigations of patients with vasculitis were prompted by the recognition of arteritis, which in fact could be seen grossly as modular enlargements in the arteries within the parenchyma and even in main visceral arteries such as the renal arteries, hepatic artery. There were many early reports. Certainly Karl Rokitansky described patients with what was in fact arteritis in his discussions of patients with aneurysms. But Kussmaul and Maier in 1866 really published one of the first detailed descriptions of vasculitis in patients. In the one patient that they described most carefully, the involvement was predominantly, at least, within arteries and could be seen grossly; but microscopically, it involved very small vascular radicals as well.
In their patient the presentation was similar to what I’m sure you’ve seen in your own patients. There were the non-specific manifestations of a systemic inflammatory process–fever, anorexia, weakness. There were also indications of vascular involvement in the tissues–myalgia, paresthesia, abdominal pain, cutaneous nodules, and there was oliguria. The gross pathology, as I mentioned and, as was illustrated here in the article by Kussmaul and Maier, was predominantly nodular thickenings along arterial radicals. Histologically this was shown to be inflammation and necrosis.
Renal involvement by polyarteritis nodosa. Note dark thrombosed pseudoaneurysms and pale peripheral infarcts.
- Gross changes of medium-sized vessel vasculitis
This is a similar presentation to what was seen and illustrated by Kussmaul and Maier. In this photograph, you can see that these kidneys have large aneurysms filled with clotted blood. These are really not true aneurysms; they are pseudo- aneurysms because actually the inflammatory process has eroded through the vessel wall and into the adjacent parenchyma. So it’s not just a dilation of a vessel–it’s an erosion through a vessel by this necrotizing process. Of course, this process can occlude the arterial arteries that are involved. You can see in the periphery here a number of infarcts, which is a complication of arteritis affecting the larger vessels in the kidney. In fact, there was rupture of one of the aneurysms. This patient actually died from massive hemorrhage into the retroperitoneal and peritoneal cavities. In this patient you can also see the typical nodular inflammatory lesion of polyarteritis nodosa as it’s called today.
- Microscopic changes in the pancreas: polyarteritis nodosa
Here we can see an artery within the pancreas. At this point the walls have been eroded through and there is this large pseudo-aneurysm filled with thrombotic material. This process was initially called periarteritis nodosa by Kussmaul and Maier, but soon after the term polyarteritis nodosa became more popular, and nowadays it is really the preferred term because many different vessels are involved and it is really a transmural process, not a perivascular process.
- It is found that some vasculitis has granulomatous changes
For over 50 years almost anyone with necrotizing arteritis was called periarteritis nodosa or polyarteritis nodosa. Anybody with necrotizing arteritis was put into that category. But by the 30s, it was becoming clear that there were various patients who had distinctive features in addition to the systemic necrotizing vasculitis that warranted separation into a different category.
Klinger in the early 30s and later his schoolmate, Wegener, described this pattern of granulomatous inflammation associated with the necrotizing vasculitis that we now call Wegener’s granulomatosis. In this process there is systemic small-vessel vasculitis with necrosis. There is arterial involvement frequently with necrosis, and there is granulomatous inflammation, often in the respiratory tract–either the lung or the upper respiratory tract–with a very necrotizing character to it but with scattered multi-nucleated giant cells that have lead to the designation granulomatosis.
Necrotizing and granulomatous arteritis in the lung of a patient with Churg-Strauss syndrome.
- Granulomatous inflammation, vasculitis, and eosinophilia
Another variant of this granulomatous inflammation associated with necrotizing vasculitis was described by Churg and Strauss and is now designed Churg-Strauss Syndrome. In these patients there was an associated asthma as well as peripheral eosinophilia, and sometimes their vasculitic and granulomatous process was preceded by a eosinophilic pneumonia or an eosinophilic enteritis. So, again, there was a subset of patients that initially were considered polyarteritis nodosa with asthma. Eventually the terminology evolved such that there was a more specific designation, Churg-Strauss Syndrome, for what appeared to be a clinically pathologic process distinct from usual polyarteritis nodosa.
- The beginnings of a classification emerge
So you can see that from the initial single category of necrotizing arteritis, some entities with specific features were being separated. At this point we really had still polyarteritis nodosa, Wegener’s granulomatosis, and Churg-Strauss Syndrome. Zeek and Godman and Churg in the early 50s, and in fact beginning in the late 40s, added some substantial insight into the categories of necrotizing vasculitis. Early classification systems: Zeek (1948, 1952)
Although Zeek’s 1952 article is better known, her 1948 article really describes more carefully her perception of necrotizing vasculitis. And what she concluded was that there were two major forms of necrotizing vasculitis. There was what had been described, she felt, by Kussmaul and Maier that she was at that time calling periarteritis nodosa that had involvement of arteries but had no involvement of the lungs, and it had no involvement of vessels smaller than arteries.
Clinical features of many vasculitis syndromes overlap, and these abnormal conditions are heterogeneous—complicating the diagnosis and classification of affected subjects. Both this heterogeneity and lack of causal identification have hindered the development of a classification system. Available classification schemes are chiefly descriptive, and consensus is occasionally lacking on essential features of each condition.
The Chapel Hill conference provided an organization and classification of vasculitis based principally on the size of the affected vessel (Figure 1). Controversy continues about small-vessel necrotizing arteritis, currently considered microscopic polyangiitis (MPA) in the Chapel Hill classification scheme. Some authorities believe MPA is a component of polyarteritis nodosa. However, MPA should not be confused with small-vessel necrotizing vasculitis, which characterizes Wegener’s granulomatosis and Churg-Strauss syndrome. Neither should MPA be confused with leukocytoclastic vasculitis, typically seen in Henoch-Schonlein purpura or hypersensitivity vasculitis. Usually, small-vessel necrotizing vasculitis affects arterioles, venules, and capillaries. Leukocytoclastic vasculitis affects capillaries and venules generally found in the skin. MPA affects vessels of various sizes, including small arteries, but not muscular arteries as in polyarteritis nodosa. Two series of randomized controlled trials have helped to define the classification of vasculitic syndromes, using ANCA and effective therapeutic regimens.
Primary Vasculitis Syndromes
- Wegener’s granulomatosis
- Churg-Strauss syndrome
- Polyarteritis nodosa
- Microscopic polyangiitis
- Giant Cell arteritis
- Takayasu’s arteritis
- Henoch-Schöenlein purpura
- Idiopathic cutaneous vasculitis
- Essential mixed cryoglobulinemia
- Behcet’s syndrome
- Isolated vasculitis of the central nervous system
- Cogan’s Syndrome
Secondary Vasculitis Syndromes
- Drug induced vasculitis
- Serum sickness
- Vasculitis associated with other primary diseases
- Infection e.g. Hepatitis B associated polyarteritus nodosa
Autoimmune disease (e.g. systemic lupus erythematosus, Sjögren’s Syndrome)
- An example of small-vessel necrotizing arteritis.
How the concept of hypersensitivity angiitis evolved
There are group of patients who had “lesions and small intrinsic venules, arterioles, and small arteries of the viscera, including the lung.” Necrotizing glomerulonephritis as a frequent feature of this lesion, and in fact said that “involvement of arteries that were larger was very rare in these patients.” This hypersensitivity angiitis because a number of her patients had been treated with sulfa drugs, but of course anyone with inflammatory pulmonary disease at that point in time would have gotten sulfa drugs. Experimental models of vasculitis induced by positioning silk around the kidneys, which was then felt to be induction of vasculitis by an allergic response to that foreign material. Its called hypersensitivity angiitis. This term, unfortunately thereafter was used to described many different forms of vasculitis, some with more or less evidence for an allergic pathogenesis.
Zeek’s 1952 classification system for vasculitis
Zeeks 1952 article proposed an actual classification system for vasculitis: What she called periarteritis nodosa; hypersensitivity angiitis, which is a small-vessel necrotizing vasculitis; she was aware of the allergic granulomatosis and angiitis that we now call Churg-Strauss Syndrome
The apparently as not aware of Wegener’s granulomatosis being a type; and also was aware that patients with rheumatic diseases developed forms of vasculitis; and was aware of the large vessel form of vasculitis called temporal arteritis, which is now designated giant cell arteritis because it doesn’t always affect just the temporal arteries.
Godman and Churg’s contributions
Godman and Churg also looked at systemic vasculitides. Of course, Churg had been involved with Strauss earlier in describing Churg-Strauss Syndrome. They came to some conclusions in 1954 which are basically, in my opinion, where we are today. They recognized again that periarteritis nodosa, as it was designated, affected mainly arteries and grossly visible arteries. But they concluded that there was a more common form of vasculitis that they referred to as the “microscopic form of periarteritis nodosa.” They concluded that, in fact, this was the same category of vasculitis that Zeek was calling hypersensitivity angiitis. But they pointed out that there really was not good evidence for allergy in these patients and that isn’t a good terminology. So they preferred the term “microscopic form of periarteritis.” They also, of course, were aware of Wegener’s granulomatosis. In this 1954 article, they clearly described the major triad of Wegener’s granulomatosis with systemic necrotizing angiitis, as they called it; necrotizing glomerulonephritis; and, of course, the granulomatous inflammation. And they also were, of course, aware of Churg-Strauss Syndrome since Churg had just been involved with describing this earlier. They concluded that because of the pathologic similarity, especially of the underlying small-vessel vasculitis, that Wegener’s granulomatosis, Churg-Strauss Syndrome, and microscopic form of periarteritis were related and were distinct from and probably pathogenetically distinct from periarteritis nodosa or what we call polyarteritis nodosa. More recent data that review later supports this position that they put forward in 1954. These do appear to be related because they all are associated with ANCA. This process [polyarteritis nodosa], believe distinct and now uncommon as we’ve pulled away from it many more specific forms of vasculitis.
Small coronary artery with segmental necrosis and inflammation in a patient with Kawasaki disease.
In the 1960s, the final major category of necrotizing vasculitis was separated from the polyarteritis nodosa group, and this is Kawasaki’s disease. Up until this point, there were other descriptions of this process sometimes referred to as infantile form of polyarteritis nodosa because Kawasaki’s disease occurs most frequently in young children. However, Kawasaki’s disease has another very distinctive component, and this is the mucocutaneous lymph node syndrome. So basically the diagnostic characteristic that separates Kawasaki’s disease from polyarteritis nodosa is this mucocutaneous lymph node syndrome with erythematous and scaly mucosa and skin, especially on the digits, with a lymphadenopathy and with this necrotizing vasculitis that has a predilection for the coronary arteries and can produce aneurysms with thrombosis and myocardial infarction. The necrotizing lesion is similar to that of polyarteritis nodosa, although there are some subtle differences in general — a little less fibrinoid necrosis, a little more cellular character to the initial injury.
It is realized that vasculitis affects vessels other than arteries
Now all of this investigation up until this point has been stimulated by arteritis. So investigators were looking at patients who clearly had involvement of the arteries. But there was a parallel development of categorization of patients with evidence for vasculitis that was taking place based on manifestations of small-vessel vasculitis that was affecting vessels other than arteries.
Purpura caused by small vessel vasculitis, for example, any form of ANCA-vasculitis, such as microscopic polyangiitis, Wegener’s granulomatosis, or Churg-Strauss syndrome; or immune complex small vessel vasculitis, such as Henoch-Schönlein purpura or cryoglobulinemic vasculitis.
Purpura and vasculitis: Henoch-Schonlein purpura
The major manifestation that lead to this sequence of parallel but eventually intersecting investigations of patients with vasculitis was purpura. And so in the literature, actually from the Greeks and probably before, there have been clinical descriptions of purpura.
Dermal leukocytoclastic angiitis, which is the most frequent pathologic lesion causing vasculitic purpura; and can be a component of many types of small vessel vasculitis.
Some of the earliest elucidations, however, of the syndrome of purpura, which was found eventually to have a substantial renal component, were carried out by Schonlein and later by Henoch. In fact, Henoch gave the more careful description of the full spectrum of small-vessel involvement in what is now sometimes called Henoch-Schonlein purpura. Clearly at the point that they were describing the syndrome, a number of small-vessel vasculitis categories were present in the patients they investigated. Also at the turn of the century, Osler made some major contributions in the evaluation of patients with small-vessel vasculitis and was one of the first to recognize how often renal involvement occurred and how severe it might be in patients with purpura, abdominal pain, and nephritis. Now the reason I think that Osler saw the more severe renal involvement was he was seeing more adults.
Henoch was a pediatrician so most of the patients he saw were children. He saw what today we would call Henoch-Schonlein purpura, with purpura, abdominal pain, and nephritis; whereas Osler was seeing adults, many of whom had microscopic polyangiitis with purpura, abdominal pain, and nephritis. His patients tended to be more severe. In any event, those investigations of patients with purpura pointed out that small-vessel vasculitis can affect the skin, can affect the gut, can affect the kidneys; also peripheral nephropathies were present in some of those patients, and that involvement was recognized.
Massive pulmonary hemorrhage in a patient with Goodpasture’s syndrome.
- Involvement of the lung in vasculitis
The next organ system that was recognized to be affected by small-vessel vasculitis in a pattern other than arteritis and granulomatous inflammation was the lung, with hemorrhagic capillaritis causing massive hemorrhage in some patients. Goodpasture is credited with one of the earliest descriptions of a patient with this so-called pulmonary-renal vasculitic syndrome; a patient who, following a flu-like illness developed severe pulmonary hemorrhage and severe glomerulonephritis. Actually at postmortem examination, this patient had small-vessel vasculitis in the spleen and the gut as well. This patient probably had ANCA- associated microscopic polyangiitis. However, Goodpasture’s syndrome, the designation, is now used primarily for patients with evidence for anti-basement membrane disease, as I will return to in a moment.
- It is realized that the spectrum of vascular injury can be quite broad
So at this point then from investigations of patients with clinical manifestations of small-vessel vasculitis, it was clear that the spectrum of necrotizing vascular injury was quite broad. Arteries could be involved, venules could be involved, capillaries could be involved in the glomeruli, producing necrotizing glomerular injury, and capillaries in the lungs could be involved. So many tissues could be involved. This was a very complex problem of classification at that point because you had this broad spectrum of vascular and organ system involvement and any number of names that had been applied in varying ways to these. It was quite confusing, not that it’s not still confusing.
- Antineutrophil Cytoplasmic Antibodies
- The role that immune complexes play is appreciated
Fortunately some other modalities of diagnostic evaluation came into the picture in the 60s, in particular, and 70s. Immunohistology demonstrated that at least some of these patients with small-vessel vasculitis had immune complexes in the vessel walls, for example, here in the dermis of a patient with leukocytoclastic angiitis histologically and purpura clinically.
A number of immune complex vasculitides were subsequently recognized. Henoch-Schönlein purpura has been redefined and restricted to those patients with IgA-dominant immune complexes as the cause of their small-vessel vasculitis. By that definition, it occurs primarily in children and usually has a good outcome. Cryoglobulinemia vasculitis was recognized by McClusky and his associates initially and, of course, is the result of cryoglobulins, especially Types II and III cryoglobulins localizing in small vessels and inciting inflammation. Lupus can, on occasion, have a systemic vasculitis; rheumatoid arthritis patients occasionally have an immune complex vasculitis; serum sickness vasculitis; infection-associated vasculitis; paraneoplastic vasculitities; some drug-induced vasculitides can show evidence for immune complex deposition.
Allergic vasculitis is hypersensitivity to a drug or foreign substance that leads to inflammation and damage to blood vessels of the skin. Alternative Names Vasculitis – allergic hypersensitivity; Cutaneous leukocytoclastic vasculitis. Allergic vasculitis is caused by an allergic reaction to a drug or other foreign substance.
- Skin lesions usually located on legs, buttocks, or trunk
- Blisters on the skin
- Urticaria (hives), may last longer than 24
Pauci-immune vasculitis is appreciated
For a while it was considered that possibly most, maybe even all, small-vessel vasculitides were caused by immune complex deposition or anti-basement membrane antibodies. And, of course, when you look at the glomerular involvement, which is frequent in patients with small-vessel vasculitis, you certainly do see some patients with granular staining indicative of an immune complex disease and linear staining indicative of anti-basement membrane disease. However, it became apparent to any number of investigators that the involved vessels other than glomeruli as well as the glomeruli in many patients with small-vessel vasculitis, especially patients with Wegener’s granulomatosis and microscopic polyangiitis, did not have staining for immunoglobulin or complement. So this paucity of staining was somewhat of a problem in explaining the pathogenesis.
Prevalence of immune complexes in vasculitis
And in fact, these patients with pauci-immune vasculitis were quite common. For example, in this analysis of patients evaluated in my laboratory, you can see that the pauci-immune category is about equal to the immune complex category and much more frequent that anti-GBM disease if you look at all patients with inflammatory glomerulonephritis. And as you look at more and more severe glomerulonephritis, the frequency of this pauci-immune category goes up even more. So if you look at those patients who have greater than 50 percent of their glomeruli involved with crescents, this pauci-immune category is the most common. And, in fact, if you look at those few patients in whom you see necrotizing vasculitis in addition to glomerulonephritis in the kidney, there is a strong predilection here for the pauci-immune category.
Pauci-immune glomerulonephritis and ANCA positivity
Also in older patients, as has been seen here in Scandinavia by Pedersen and her associates in Stockholm, the frequency of this pauci-immune pattern and in fact this ANCA-associated disease pattern goes up. You can see here in this particular cohort, 90 percent of the patients were ANCA positive. So the pauci-immune category of glomerulonephritis and small-vessel vasculitis almost equates with ANCA vasculitis and glomerulonephritis.
As will be discussed later in detail by Jörgen Wieslander, ANCA specificity, as is well known to this group, in patients with glomerulonephritis vasculitis breaks down primarily into patients with anti-proteinase 3 specific antibodies that react with the cytoplasm and cause the C ANCA staining pattern and anti-myeloproxidase specific autoantibodies that react with antigen that is redistributed to the nucleus artifactually during preparation of the substrate if you use alcohol-fixed neutrophils. So these two ANCA specificities then mark a subset of small-vessel vasculitis that probably have a related pathogenesis.
ANCA vasculitis: glomerular and extrarenal involvement patterns
If you look at all patients with ANCA- positive glomerulonephritis, some of them apparently have involvement of no other tissues from all of the evidence that you can collect. But most patients with ANCA-positive glomerulonephritis have evidence for involvement of other viscera. The diagnostic challenge in these patients is to categorize those patients into some specific set if possible. This may be a somewhat academic exercise because, as we will discuss some later, the treatment may be very similar if not identical for all of these categories. So the main step is initially realizing that it is an ANCA-positive necrotizing small-vessel vasculitis and possibly proceeding with treatment at that point and trying to categorize them further. If there is no systemic involvement, just ANCA glomerulonephritis, some prefer the term renal-limited vasculitis. If there is involvement of the respiratory tract or elsewhere with granulomatous inflammation, then Wegener’s granulomatosis is the proper designation if there is no history of asthma. If there is a history of asthma, then Churg-Strauss syndrome. In these patients, the eosinophilia is usually more than 10 percent. If there is no evidence for Wegener’s granulomatosis or Churg-Strauss syndrome, then the term that I would suggest is microscopic polyangiitis. I believe this is preferable to microscopic polyarteritis because many of these patients have no apparent involvement of arteries at all. They may have pulmonary capillaritis, they may have postcapillary venulitis in the skin, they may have glomerulonephritis, but they may not have arteritis. So the term microscopic polyangiitis is a better generic term.
With respect to the association of the autoantibody specificities, various cohorts have been analyzed. This is an analysis of 111 patients from our cohort of ANCA-diseased patients. There is a predominance of the anti-PR3 specificity in patients with the Wegener’s granulomatosis phenotype, but at least in our experience at this point, about one-third of these patients have anti-MPO specificity. In the microscopic polyangiitis patients, there is about an equal frequency of anti-MPO and anti-PR3 antibodies with possibly a little bit of predominance of anti-MPO specificity. In the patients with renal-limited disease, there is a very striking predilection for the anti-MPO.
Chapel Hill nomenclature system
The categorization of small-vessel vasculitis in patients with renal disease can usually be accommodated by what is sometimes referred to as the Chapel Hill nomenclature system, which categorizes some of these major forms of small-vessel vasculitis as Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, all associated with ANCA; Henoch-Schönlein purpura, with IgA dominant immune complexes; cryoglobulinemic vasculitis, with circulating cryoglobulins and cryoglobulins in the tissues; and then occasional patients who have small-vessel vasculitis just confined to the skin. These patients may have a self-limited, benign course, but some of these patients will ultimately be found to have systemic involvement including the kidney.
Vasculitides not on the above list
Of course, there are other forms of small-vessel vasculitis not accommodated in this particular list that I’ve described earlier: lupus- associated vasculitis, some forms of drug-induced vasculitis, infection-associated vasculitis. But in all of these circumstances, I think the initial approach should be to recognize that your patient has a small-vessel vasculitis and then as best you can to pursue additional diagnostic procedures, for example immunohistology on biopsy tissue, serology, to put them into a more specific category because that will impact substantially on the appropriate treatment regimen.
Pathophysiology Giant-cell vasculitis typically affects large arteries that have an elastic lamina. Most commonly, these vessels are part of the carotid artery or its branches. But this is a systemic disorder, and any large artery may be affected. Giant-cell arteritis is histologically characterized by features of a panarteritis. This panarteritis is accompanied by inflammatory, mononuclear infiltrates inside the vessel wall, which usually focus on the internal, elastic lamina. Multinucleated giant cells are typical. This pathophysiology suggests a cell-mediated immune response, probably specific for antigens in the elastic lamina. The pathophysiology is supported by distinct cytokine patterns; detection of increases in tumor necrosis factor, IL-6, IL-1β, IL-2 and IFN-γ; and identification of T lymphocytes expressing specific antigen receptors with restricted clonal expansion. Temporal arteritis or cranial arteritis occurs almost exclusively in individuals more than 50 years of age and is more common in Caucasian women of northern-European heritage. Familial aggregation and an association with select human leukocyte antigen (HLA) alleles, particularly HLA-DR4, support a genetic predisposition for the disease. Polymyalgia rheumatica, a syndrome accompanied by symmetrical musculoskeletal aching, often occurs with giant-cell vasculitis, but this condition may occur alone and is twice as common as giant- cell vasculitis.
Diagnosis The clinical symptom that makes giant-cell vasculitis likely to be encountered by allergists/immunologists is headache. This headache is easily confused with the other facial and cranial complaints that are sometimes attributed to sinus disease. The headache is often more severe than a patient’s prior headaches, is described as somewhat boring in character, and may be unilateral. Scalp pain, particularly with hair brushing or with chewing, are highly suggestive of the diagnosis. Other manifestations include fatigue, malaise, anorexia, weight loss, subjective fever, or sweats, along with pain in the axial and proximal muscle extremities. Initial physical findings are limited and include tenderness of the temporal artery and occasionally over one or more branches of the affected arteries. As with other vasculitic syndromes, ischemia is the major complication. In this case, ischemia often affects the ophthalmic arteries—with blindness from optic nerve ischemia being the most common and severe complication.
Laboratory findings include increased erythrocyte sedimentation rate, normochromic or slightly hypochromic anemia, increased gamma globulin and complement, elevated C-reactive protein, increased blood IL-6 concentration, and mildly abnormal liver-function. Most of these findings reflect a systemic response to release of inflammatory cytokines, particularly IL-1, IL-6, and tumor necrosis factor.
Diagnosis is usually confirmed by microscopic examination of a temporal artery segment (Figure 4). A biopsy of 3-5 cm of vascular tissue will optimize diagnostic potential. Bilateral biopsies slightly increase diagnostic yield. Treatment may be initiated for as long as a week to 14 days before biopsy without significantly modifying pathologic findings. This may be important to a clinician who might begin treatment before obtaining a biopsy to minimize the chance of irreversible blindness if the biopsy is postponed.
Treatment Treatment of giant-cell vasculitis is similar to that for other forms of complicated vasculitis, except that oral glucocorticoids alone are more likely to be sufficient. Treatment is usually initiated at 40-60 mg/day until the disease is controlled, as manifested by resolution of symptoms and normalization of blood abnormalities—particularly anemia and ESR. Tapering of the glucocorticoid therapy should be started as soon as possible to minimize systemic side effects, as treatment may be necessary for up to 2 years, usually on an every-other-day schedule. Weekly methotrexate has permitted a reduction or discontinuation of glucocorticoid therapy in 2 randomized trials, allowing control of the disease with limitation of side effects such as osteoporosis. Giant-cell vasculitis has fewer tendencies to relapse following remission compared to ANCA-positive vasculitis. Polymyalgia rheumatica is best treated with low-dose prednisone (usually 10-15 mg daily) for 6-12 months.
Summary Allergists/immunologists frequently see hypersensitivity vasculitis associated with viral infection and drug allergy. A consideration of this syndrome often enters into the differential diagnosis between urticaria and urticarial vasculitis. Allergists/immunologists commonly encounter ANCA-positive vasculitis because these conditions affect the lung and upper airway. Churg Strauss vasculitis occurs in subjects with a history of asthma and is characterized by pulmonary infiltrates and eosinophilia. Wegener’s vasculitis and Churg Strauss vasculitis often result in a persistent sinusitis. Microscopic polyangiitis is also associated with pulmonary infiltrates and hemoptysis. Finally, the headache found in giant-cell vasculitis may be confused with sinusitis, introducing this condition into the differential diagnosis of individuals being evaluated for sinus complaints.
Assessment and treatment of vasculitis remains empirical because of the absence of known etiologies and pathophysiology. The value of combining oral glucocorticoid therapy with cyclophosphamide has stood the test of time in Wegener’s granulomatosis, but disease relapse and efforts to limit side-effects greatly spur our search for other therapies.
Many alternatives for vasculitis treatment are available but inadequate experience prevents definitive recommendations. Since vasculitic syndromes are relatively rare, our potential of gathering sufficient numbers of patients for double-blind trials is low. Therefore, each clinician must weigh risks against benefits in various treatment options without the advantage of definitive trial data. Treatment choices remain a challenge in managing subjects diagnosed with vasculitis.
Vasculitis Associated with Antineutrophil Cytoplasmic Antibody (ANCA)
Pathophysiology Vasculitis varieties associated with Antineutrophil Cytoplasmic Antibody (ANCA) include Wegener’s granulomatosis, Churg-Strauss Vasculitis, and microscopic polyangiitis. The description of ANCA and its association with specific vasculitis syndromes have modified our clinical evaluation of vasculitis and proposed pathophysiologic mechanisms. Cytoplasmic immunofluorescence of fixed neutrophils (c-ANCA)— demonstrating human autoantibody binding—is manifest in cases of Wegener’s granulomatosis. Perinuclear staining (p-ANCA) is characteristic in Churg-Strauss syndrome, microscopic polyangiitis, and progressive glomerulonephritis with vasculitis. Exceptions occur with staining patterns. For example, p-ANCA may be seen in about 5% of Wegener’s granulomatosis cases. ANCA occurs in subjects without vasculitis and is absent in some individuals with these conditions. Thus, the detection of ANCA supports but does not establish a diagnosis, and the absence of ANCA does not eliminate the diagnosis of vasculitis of these types. Measuring antibodies to specific neutrophil antigens enhances the specificity of ANCA results and improves the prognostic value of titer changes in predicting changes in disease activity.
Antimyeloperoxidase antibodies are characteristic in microscopic polyangiitis or Churg-Strauss syndrome (associated with p-ANCA), and anti-proteinase 3 is more specific for Wegener’s granulomatosis (associated with c-ANCA). The concentration of ANCA may be used to monitor disease activity and assist decision-making related to therapeutic dose reduction. The addition of monitoring levels of antibodies to specific neutrophil enzymes—such as elastase, proteinase 3 or myeloperoxidase—may enhance the reliability of ANCA changes in predicting changes in disease activity.
ANCA may activate neutrophils, resulting in initiation or augmentation of immunologic response and blood-vessel damage. Therefore, treatments directed toward reducing ANCA may minimize disease activity. The importance of ANCA in the pathophysiology of the associated vasculitis is unproven but suspected.
Diagnosis Wegener’s granulomatosis typically affects the upper airway, lung, and kidney. Involvement of the airway is the main reason that allergists/immunologists will encounter this vasculitic syndrome. Ninety percent or more of affected subjects will have ear, nose, or throat involvement including persistent sinusitis, nasal crusting or bleeding, otitis media, hearing loss, and ear pain. Pulmonary involvement occurs in more than 80% of affected subjects, usually showing nodules, infiltrates, or hemoptysis. Symptoms of Churg-Strauss vasculitis are likely to help in the differential diagnosis of persistent sinus disease, difficult-to-treat asthma, allergic bronchopulmonary aspergillosis, eosinophilia, and increased blood IgE. Churg-Strauss vasculitis usually occurs in individuals with a history of asthma and allergy or allergic-like disease, overlapping with the majority of patients seen by an allergist or immunologist (). Microscopic polyangiitis or small-vessel necrotizing vasculitis is characterized by pulmonary involvement, often with hemorrhage. Asthma is not characteristic of microscopic polyangiitis.
Since all three of these syndromes share a tendency for ANCA positivity and airway involvement, allergists/immunologists are likely to encounter individuals in which these syndromes are considered in the differential diagnosis. The prognosis of all three is poor without suitable treatment. So, allergists/immunologists emphasize the need for awareness and prompt diagnosis.
Treatment of ANCA Associated Vasculitis Mean survival time of untreated subjects with Wegener’s granulomatosis (WG) is 5 months. Allergists/immunologists see more than 90% mortality rate within 2 years of diagnosis for patients without therapy. Similarly, the 5-year prognosis for survival of untreated Churg-Strauss vasculitis and microscopic polyangitis is 25% or less. With treatment, patients in all three vasculitis syndrome groups experience a 5-year survival rate of greater than 70%.
Glucocorticoid therapy alone is marginally effective in suppressing these diseases, with median survival of slightly more than one year for patients with Wegener’s granulomatosis. Controlled trials have demonstrated that a combination of oral prednisone, 1-1.5 mg/kg/day and oral cyclophosphamide, 2mg/kg/day, is effective in inducing remissions and permitting tapering of therapy over several years in the majority of Wegener’s granulomatosis studies. Prednisone dosage is tapered to every other day and the cyclophosphamide gradually also tapered over 6-24 months. Conversion to alternative immunosuppressive therapy, particularly with weekly methotrexate after 6 months of successful induction therapy, may maintain clinical response without increasing the risk of bladder cancer—a side effect of oral cyclophosphamide treatment. Recommendations for therapy of other forms of ANCA-associated vasculitis, such as Churg-Strauss syndrome or microscopic polyangiitis, are less secure because we lack sufficient controlled trials. However, many clinicians use treatments similar to those studied in Wegener’s granulomatosis.
Relapses of Wegener’s granulomatosis after remission, along with the cumulative adverse effects produced by both the prednisone and cyclophosphamide administration, have stimulated the search for alternative treatments. A randomized study demonstrated clinical benefits of monthly, pulse-therapy with cyclophosphamide. This study showed a reduction of side effects and a 57% reduction of total cyclophosphamide dose needed for disease control. The intravenous treatment group experienced significantly fewer infections, less leukopenia, and a possible reduction of gonadal toxicity as a result of decreased levels of follicle-stimulating hormone. Also, intermittent, intravenous cyclophosphamide is associated with less bladder toxicity than daily, oral therapy. Recent onset of disease, presence of renal involvement and absence of granulomas in the lung and airway characterize a cohort of subjects that shows better response to intravenous cyclophosphamide. Daily treatment with oral cyclophosphamide appears to be more effective than monthly treatment with intravenous cyclophosphamide. An oral combination of trimethoprim and sulfamethoxazole reduces relapse rates in Wegener’s granulomatosis, sparing additional cytotoxic and glucocorticoid therapy. Intramuscular, depot-injections of corticosteroid may also reduce corticosteroid side effects without significantly compromising clinical response. Weekly, oral, pulse–administration of methotrexate is also effective in controlling Wegener’s granulomatosis and is a potential consideration if cyclophosphamide toxicity or adverse effect to gonads is an overriding concern. Methotrexate is also recommended after the first 6 months of cyclophosphamide administration to ease tapering of the cyclophosphamide, thereby minimizing bladder toxicity. Methotrexate therapy is not recommended for severe, immediately life-threatening disease. Limited data support the efficacy of mycophenolate mofetil and calcineurin inhibitors, such as cyclosporine and tacrolimus, in the treatment of necrotizing vasculitis. Inhibitors of tumor necrosis factor—such as etanercept—have not been found to be effective in Wegener’s granulomatosis. Intravenous gamma globulin may be of some value in Churg-Strauss vasculitis.
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